Quinolinone compound and use thereof

Abstract

Provided herein are a quinolinone compound, pharmaceutical composition thereof, and use of the compound or the pharmaceutical composition in drug preparation, the drug being used to prevent, manage, treat or relieve diseases related to HIF and/or EPO of a patient, including anemia, vascular disease, myocardial ischemia, dysmetabolism, or for wound healing.

What is claimed is: 
     
       1. A compound having Formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof, 
       
         
           
           
               
               
           
         
         wherein, 
         R 1  is C 1-4  alkyl, and wherein C 1-4  alkyl is optionally substituted with one, two, three or four substituents independently selected from C 3-6  cycloalkyl, or C 2-5  heterocyclyl; 
         each of R 2 , R 3 , R 4  and R 5  is independently H or -L-R 10 , with the proviso that R 2 , R 3 , R 4  and R 5  are not H at the same time; 
         wherein each L is independently —(CR 11 R 12 ) p —O—, —(CR 11 R 12 ) p —S(═O) n —, —(CR 11 R 12 ) p —N(R 13 )—, or —(CR 11 R 12 ) p —C(═X)—; 
         wherein each X is independently O or S; 
         each R 11  and R 12  is independently H, halogen, cyano, hydroxy, mercapto, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, C 3-10  cycloalkyl, C 2-9  heterocyclyl, C 6-10  aryl or C 1-9  heteroaryl, and wherein optionally each of C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, C 3-10  cycloalkyl, C 2-9  heterocyclyl, C 6-10  aryl and C 1-9  heteroaryl is independently substituted with one, two, three or four substituents independently selected from oxo (═O), halogen, hydroxy, amino, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, acyl, sulfonyl, C 3-8  cycloalkyl, C 2-7  heterocyclyl, C 6-10  aryl or C 1-9  heteroaryl; 
         each R 13  is independently H, C 1-6  alkyl, C 3-10  cycloalkyl, C 2-9  heterocyclyl, C 6-10  aryl or C 1-9  heteroaryl, and wherein optionally each of C 1-6  alkyl, C 3-10  cycloalkyl, C 2-9  heterocyclyl, C 6-10  aryl and C 1-9  heteroaryl is independently substituted with one, two, three or four substituents independently selected from oxo (═O), cyano, nitro, halogen, hydroxy, amino, mercapto, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, acyl, sulfonyl, C 3-8  cycloalkyl, C 2-7  heterocyclyl, C 6-10  aryl or C 1-9  heteroaryl; 
         each R 10  is independently —OR 14 , —NR 15 R 16 , —C(═O)NR 15 R 16 , —N(R 15 )C(═O)R 17 , —C(═O)R 17 , —S(═O) n R 18 , —S(═O) 2 NR 15 R 16 , —N(R 15 )S(═O) 2 R 18 , C 3-10  cycloalkyl, C 3-10  cycloalkyl-C 1-6 -alkyl, C 2-9  heterocyclyl, C 2-9  heterocyclyl-C 1-6 -alkyl, C 6-10  aryl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl or C 1-9  heteroaryl-C 1-6 -alkyl, and wherein optionally each of C 3-10  cycloalkyl, C 3-10  cycloalkyl-C 1-6 -alkyl, C 2-9  heterocyclyl, C 2-9  heterocyclyl-C 1-6 -alkyl, C 6-10  aryl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl and C 1-9  heteroaryl-C 1-6 -alkyl is independently substituted with one, two, three or four substituents independently selected from oxo (═O), halogen, hydroxy, mercapto, amino, nitro, cyano, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, acyl, sulfonyl, C 3-10  cycloalkyl, C 2-9  heterocyclyl, C 6-10  aryl or C 1-9  heteroaryl; 
         wherein each R 14 , R 16 , R 17  and R 18  is independently C 3-10  cycloalkyl, C 3-10  cycloalkyl-C 1-6 -alkyl, C 2-9  heterocyclyl, C 2-9  heterocyclyl-C 1-6 -alkyl, C 6-10  aryl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl or C 1-9  heteroaryl-C 1-6 -alkyl; 
         each R 15  is independently H or C 1-6  alkyl; 
         R 6  is hydroxy; 
         R 7  is H; 
         each R 8  and R 9  is H; 
         k is 1; 
         each m is independently 1, 2, 3 or 4; 
         each n is independently 0, 1 or 2; and 
         each p and q is independently 0, 1, 2, 3 or 4. 
       
     
     
       2. The compound according to  claim 1 , wherein
 each L is independently —(CR 11 R 12 ) p —O—, —(CR 11 R 12 ) p —S(═O) n —, or —(CR 11 R 12 ) p —N(R 13 )—; 
 wherein each R 11  and R 12  is independently H, fluorine, chlorine, bromine, C 1-4  alkyl, C 1-4  haloalkyl, C 3-6  cycloalkyl, C 2-5  heterocyclyl, C 6-10  aryl or C 1-5  heteroaryl, and wherein optionally each of C 1-4  alkyl, C 1-4  haloalkyl, C 3-6  cycloalkyl, C 2-5  heterocyclyl, C 6-10  aryl and C 1-5  heteroaryl is independently substituted with one, two, three or four substituents independently selected from oxo (═O), fluorine, chlorine, bromine, hydroxy, —NH 2 , methylamino, dimethylamino, methyl, ethyl, propyl, n-butyl, t-butyl, trifluoromethyl, methoxy, trifluoromethoxy, cyclopropyl, cyclopentyl, cyclohexyl, pyrrolidyl, piperidyl, morpholinyl, phenyl, naphthyl, pyrrolyl, thienyl or pyridyl; 
 each R 13  is independently H, C 1-4  alkyl, C 3-6  cycloalkyl, C 2-5  heterocyclyl, C 6-10  aryl or C 1-5  heteroaryl, and wherein optionally each of C 1-4  alkyl, C 3-6  cycloalkyl, C 2-5  heterocyclyl, C 6-10  aryl and C 1-5  heteroaryl is independently substituted with one, two, three or four substituents independently selected from oxo (═O), cyano, nitro, fluorine, chlorine, bromine, hydroxy, —NH 2 , methylamino, dimethylamino, methyl, ethyl, propyl, n-butyl, t-butyl, trifluoromethyl, methoxy, trifluoromethoxy, acetyl, methylsulfonyl, cyclopropyl, cyclopentyl, cyclohexyl, pyrrolidyl, piperidyl, morpholinyl, phenyl or pyridyl. 
 
     
     
       3. The compound according to  claim 2 , wherein
 each L is independently —O—, —S(═O) n —, or —N(R 13 )—; 
 wherein each R 11  and R 12  is independently H, C 1-4  alkyl, C 3-6  cycloalkyl, C 2-5  heterocyclyl, C 6-10  aryl and C 1-5  heteroaryl, and wherein optionally each of C 1-4  alkyl, C 3-6  cycloalkyl, C 2-5  heterocyclyl, C 6-10  aryl and C 1-5  heteroaryl is independently substituted with one, two, three or four substituents independently selected from fluorine, chlorine, bromine, hydroxy, —NH 2 , methyl, ethyl, propyl, n-butyl, t-butyl, trifluoromethyl, methoxy, trifluoromethoxy, cyclopropyl, cyclopentyl, cyclohexyl, pyrrolidyl, piperidyl, morpholinyl, phenyl, pyrrolyl or pyridyl; 
 each R 13  is independently H or C 1-4  alkyl, and wherein C 1-4  alkyl is optionally substituted with one, two, three or four substituents independently selected from cyano, nitro, fluorine, chlorine, bromine, hydroxy, —NH, methylamino, dimethylamino, methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, acetyl, methylsulfonyl, cyclopropyl, cyclopentyl, cyclohexyl, pyrrolidyl, piperidyl, morpholinyl, phenyl or pyridyl. 
 
     
     
       4. The compound according to  claim 1 , wherein
 each R 10  is independently C 3-8  cycloalkyl, C 3-8  cycloalkyl-C 1-4 -alkyl, C 2-7  heterocyclyl, C 2-7  heterocyclyl-C 1-4 -alkyl, C 6-10  aryl, C 6-10  aryl-C 1-4 -alkyl, C 1-9  heteroaryl or C 1-9  heteroaryl-C 1-4 -alkyl, and wherein optionally each of C 3-8  cycloalkyl, C 3-8  cycloalkyl-C 1-4 -alkyl, C 2-7  heterocyclyl, C 2-7  heterocyclyl-C 1-4 -alkyl, C 6-10  aryl, C 6-10  aryl-C 1-4 -alkyl, C 1-9  heteroaryl and C 1-9  heteroaryl-C 1-4 -alkyl is independently substituted with one, two, three or four substituents independently selected from oxo (═O), fluorine, chlorine, bromine, hydroxy, —NH 2 , methylamino, dimethylamino, nitro, cyano, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy, C 1-4  haloalkoxy, acyl, sulfonyl, C 3-6  cycloalkyl, C 2-5  heterocyclyl, C 6-10  aryl or C 1-9  heteroaryl. 
 
     
     
       5. The compound according to  claim 4 , wherein
 each R 10  is independently C 3-6  cycloalkyl, C 2-5  heterocyclyl, C 6-10  aryl or C 1-9  heteroaryl, and wherein optionally each of C 3-6  cycloalkyl, C 2-5  heterocyclyl, C 6-10  aryl and C 1-9  heteroaryl is independently substituted with one, two, three or four substituents independently selected from oxo (═O), fluorine, chlorine, bromine, hydroxy, —NH 2 , methylamino, dimethylamino, nitro, cyano, methyl, ethyl, propyl, n-butyl, t-butyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, acetyl, methoxycarbonyl, carbamoyl, methylsulfonyl, aminosulfonyl, methoxysulfonyl, cyclopropyl, cyclohexyl, pyrrolidyl, piperidyl, morpholinyl, oxomorpholinyl, phenyl, naphthyl, pyrrolyl, thienyl, pyridyl, pyrimidyl or quinolyl. 
 
     
     
       6. The compound according to  claim 1  having Formula (II), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof, 
       
         
           
           
               
               
           
         
       
     
     
       7. The compound according to  claim 1 , wherein
 each L is independently —O—, —S(═O) 2 —, —C(═O)N(R 13 )—, —(CR 11 R 12 )—C(═O)N(R 13 )—, or —C(═O)N(R 13 )—(CR 11 R 12 )—; 
 wherein each R 11  and R 12  is independently H, methyl, ethyl, propyl, butyl, cyclopropyl, cyclopentyl, cyclohexyl, pyrrolidyl, piperidyl, morpholinyl, phenyl or pyridyl, and wherein optionally each of methyl, ethyl, propyl, butyl, cyclopyl, cyclopentyl, cyclohexyl, pyrrolidyl, piperidyl, morpholinyl, phenyl and pyridyl is independently substituted with one, two, three or four substituents independently selected from fluorine, chlorine, bromine, hydroxy, —NH 2 , methylamino, dimethylamino, methyl, ethyl, trifluoromethyl, methoxy or trifluoromethoxy; and 
 each R 13  is independently H, methyl, ethyl, propyl or butyl. 
 
     
     
       8. The compound according to  claim 1 , wherein
 each R 10  is independently cyclopyl, cyclopentyl, cyclohexyl, oxiranyl, pyrrolidyl, pyrazolidyl, oxazolidinyl, piperidyl, morpholinyl, tetrahydropyrimidinyl, piperazinyl, oxazinanyl, phenyl, 2,3-dihydro-1H-indenyl, naphthyl, pyrrolyl, pyrazolyl, furyl, imidazolyl, oxazolyl, thienyl, thiazolyl, pyridinyl, pyrimidinyl, indolyl, dihydroindolyl, quinolyl, isoquinolyl, quinazolinyl, imidazopyridinyl, benzimidazolyl, benzofuranyl or benzothienyl, and wherein optionally each of cyclopyl, cyclopentyl, cyclohexyl, oxiranyl, pyrrolidyl, pyrazolidyl, oxazolidinyl, piperidyl, morpholinyl, tetrahydropyrimidinyl, piperazinyl, oxazinanyl, phenyl, 2,3-dihydro-1H-indenyl, naphthyl, pyrrolyl, pyrazolyl, furyl, imidazolyl, oxazolyl, thienyl, thiazolyl, pyridinyl, pyrimidinyl, indolyl, dihydroindolyl, quinolyl, isoquinolyl, quinazolinyl, imidazopyridinyl, benzimidazolyl, benzofuranyl and benzothienyl is independently substituted with one, two, three or four substituents independently selected from oxo (═O), fluorine, chlorine, bromine, hydroxy, —NH 2 , methylamino, dimethylamino, nitro, cyano, methyl, ethyl, propyl, n-butyl, t-butyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, acetyl, methoxycarbonyl, carbamoyl, methylsulfonyl, aminosulfonyl, methoxysulfonyl, cyclopyl, cyclopentyl, cyclohexyl, pyrrolidyl, piperidyl, morpholinyl, oxomorpholinyl, phenyl, pyrrolyl, thienyl or pyridyl. 
 
     
     
       9. The compound according to  claim 1  having one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       10. A pharmaceutical composition comprising the compound according to  claim 1 . 
     
     
       11. The pharmaceutical composition according to  claim 10  further comprising at least one of pharmaceutically acceptable carriers, excipients, diluents, adjuvants and vehicles. 
     
     
       12. A method for treating or lessening a disease related to hypoxia inducible factor and/or erythropoietin in a patient comprising administering to the patient a therapeutically effective amount of the compound according to  claim 1 , wherein the disease is anemia, ischemia, a vascular disease, angina pectoris, myocardial ischemia, myocardial infarction, or wound healing. 
     
     
       13. A method for treating or lessening a disease related to hypoxia inducible factor and/or erythropoietin in a patient comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition according to  claim 10 , wherein the disease is anemia, ischemia, a vascular disease, angina pectoris, myocardial ischemia, myocardial infarction, or wound healing.